The objective of this conference is to develop methods to evaluate therapies of the leukodystrophies and to apply these methods systematically. The need to do so increases each year. The gene defects in eleven of the leukodystrophies have been defined, and with the aid of magnetic resonance studies, several new entities have been delineated. The combined incidence of the leukodystrophies is in excess of 1:20 000 and an increasing number of patients are being identified. New methods of therapy of leukodystrophies, including gene therapy, are emerging and are being applied and reported on an anecdotal basis. The recent report on the status of gene therapy in general prepared by Drs. Orkin and Motulsky cites the need of objective evaluation of therapy as one of the major priorities (29). As in the past, the 1998 ULF conference will bring together clinicians and scientists concerned with the leukodystrophies who represent a large variety of disciplines who may not interact in other settings. This conference is the 17th of an annual series. The previous year's meetings received NIH support (1 R13 NS/HD 36532=01). The conferences have had a unique ambience, valued highly by the participating scientists and clinicians, in that it brings them together with affected families. The conference will have an entirely new focus, namely the evaluation of therapies. It will bring together for the first time, experts in biostatistics, ethics and in the design and implementation of multicenter clinical trials, with the clinicians and investigators who have participated in the previous conferences and include the disciplines of Pediatrics, Neurology, Genetics, Neuroscience, Neuropathology, Radiology, Biochemistry, Pharmacology and Veterinary Medicine. The aim is to design protocols that provide objective assessments of therapeutic efficacy despite the challenges presented by the rarity of individual disease entities and ethical issues. It is likely that approaches that permit evaluation of therapies for the leukodystrophies will also be applicable to other neurogenetic disorders.